39 スクアレン由来細胞毒性ポリエーテル、(+)-14-デアセチルユーリレン、(+)-ユーリレン、(-)-ロンギレンペルオキシドの全合成(口頭発表の部)
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Recently biologically active and structurally unique triterpene polyethers, which are thought to be biogenetically squalene-derived natural products, have been isolated from both marine and terrestrial plants (Figure 1). Among the polyethers, our synthetic targets in this symposium are cytotoxic 14-deacetyl eurylene (3), eurylene (5), and longilene peroxide (4), isolated from the wood of Eurycoma longifolia by Itokawa et al. (Table 1). Although the stereostructures and conformations of 3-5 have been elucidated by X-ray crystallographic analysis and spectroscopic methods, the absolute configuration of 4 had not hitherto been determined. Furthermore, total syntheses of 3 and 4 with potent cytotoxic activities have never been accomplished. Here we report the efficient and stereoselective total synthesis of (+)-14-deacetyl eurylene (3) and (+)-eurylene (5), featuring monool- and diol-differentiated chemoselective oxidative cyclizations promoted by rhenium(VII) and chromium(VI) oxo species, respectively. We also report the first enantioselective total synthesis of (-)-longilene peroxide (4) through the concept of two-directional synthesis utilizing its molecular symmetry and the determination of its absolute configuration. Our retrosynthetic analysis of 3 and 5 is illustrated in Scheme 1. These compounds have 8 asymmetric carbon centers and the trans and cis tetrahydrofuran (THF) rings. The most important key events for the total synthesis are the stereoselective construction of these THF rings and the differentiation of the 14-hydroxy group. To solve these problems, we focused on the hydroxy-directed syn oxidative cyclization of acyclic bishomoallylic alcohols promoted by rhenium(VII) and chromium(VI) oxides (Scheme 2). The treatment of triol 6 with an excess of (CF_3CO_2)ReO_3・2CH_3CN and TFAA in CH_2Cl_2/CH_3CN (9/1) at-40℃ for 1.5 hr diastereoselectively gave the expected trans THF product 16 in 84% yield (Scheme 3). On the other hand, 16 was treated with a stoichiometric amount of PCC in CH_2Cl_2 at rt for 30 min to produce (+)-14-deacetyl eurylene (3) with complete cis diastereoselectivity. Finally, selective acetylation of the 14-hydroxy group in 3 afforded another objective (+)-eurylene (5). The retrosynthetic analysis of 4 is depicted in Scheme 4. It was envisaged that the hydro-peroxy group can be introduced by oxidizing the terminal double bonds in the C_2 symmetric triTHF ether 23 with singlet oxygen. The two 2,2,5-trisubstituted THF rings in 23 will be constructed in a two-directional manner through Shi's asymmetric epoxidation of bishomoallylic alcohol 19 followed by epoxide-opening reactions. The monoTHF ether 19 will be, in turn, derived from the diepoxide 17 by extending both side chains with the C_<10> unit 18, still in the two-directional mode. According to the synthetic plan, the first asymmetric total synthesis of (-)-longilene peroxide (4) has been achieved starting from the optically active C_2 symmetric diepoxide 17 (Scheme 5). Thus, the unknown absolute configuration of longilene peroxide has been determined by this synthesis as shown in the structural formula 4.
- 天然有機化合物討論会の論文
- 2001-09-01
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